T cells controlling humoral immunity and cellular immunity are mostly CD4+T cells, which can be classified into Th (helper T cells) 1 or Th2 cells respectively, by patterns for producing cytokine. Th1 cells are known to produce IFN-γ and IL (interleukin)-2 and induce activation of macrophage, while Th2 cells are known to promote activation and antibody generation of B cells by secreting IL-4, IL-5, IL-10, IL-13 and the like. Currently, the studies related to differentiation of Th1 and Th2 has gathered attention, since they are thought to be deeply involved in the cause of immune mediated illness. Th1 has been suggested its relevance to delayed-type allergy and organ-specific autoimmune disease, whereas Th2 has been suggested its relevance to type 1 allergy and systemic autoimmune disease (SLE and others). However, because they are in antagonistic relationship each other, these diseases are expected that they can be prevented or treated by controlling Th1 or Th2. Indeed, it has been reported that administering IL-12 with an antigen for infectious disease such as leishmania induces Th1 preventing development to forfend infection.
On the other hand, PIR of mice whose expression is found in B cells, mast cells, dendritic cells and macrophages are type 1 transmembrane-type glycoprotein, belonging to immunoglobulin (Ig)-like receptor family, have 6 Ig domains extracellularly and they are classified into two subtypes of PIR-A and PIR-B by their differences of intracellular structure. The immunoglobulin (Ig)-like receptors PIR-A and PIR-B (J. Biol. Chem. 272, 7320-7327, 1997; Proc. Natl. Acad. Sci. USA. 94, 5261-5266, 1997) have been known to be the activating-type or inhibitory receptors of Ig-like receptor (IgLR) family expressing in a pair-wise fashion on a wide variety of cells mostly in the immune system (Science 290, 84-89, 2000). It has been reported that aforementioned PIR-A requires Fc receptor γ chain for its expression on cell surface and for delivery of activation signaling (J. Exp. Med. 188, 991-995, 1998; J. Exp. Med. 189, 309-318, 1999; J. Immunol. 161, 4042-4047, 1998; J. Biol. Chem. 274, 30288-30296, 1999). In contrast, PIR-B has been reported that it contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in its cytoplasmic portion and inhibits receptor-mediated activation signaling in vitro by engaging antigen receptor (BCR) on B cells and other activating-type receptors (J. Immunol. 161, 4042-4047, 1998; Proc. Natl. Acad. Sci. USA. 95, 2446-2451, 1998; J. Exp. Med. 187, 1355-1360, 1998). However, neither the physiological function nor ligand for PIR has been elucidated yet.
An object of the present invention is to provide a nonhuman model animal of Th2-mediated hyperimmune response lacking PIR-B gene function on its chromosome by which the Th2-mediated immune response mechanism and allergy onset mechanism in vivo can be analyzed and which is liable to suffer from not only hyper-response of B cells but also allergy, and to provide a method for screening an inducer/promoter or an inhibitor for Th2-mediated immune response, or a promoter or an inhibitor for PIR-A function, a method for screening a therapeutic agent for allergosis and a method for diagnosing allergosis with the use of the nonhuman model animal of Th2-mediated hyperimmune response.
The present inventors have made a keen study to elucidate physiological function for PIR-B being an inhibitory receptor pairs in the paired immunoglobulin-like receptor family, and have found that the mice lacking PIR-B gene function on its chromosome show Th2-prone humoral responses which are liable to suffer from not only hyper-response of B cells but also allergy to complete the present invention. That is, the present invention has completed based on the findings as follows. Examining above-mentioned PIR-B-deficient (PIR-B−/−) mice revealed that they have increased the number of peritoneal B-1 cells and that the B-1 cells and splenic B-2 cells of the PIR-B−/− mice showed hypersensitivity to BCR. The nonhuman model animal of Th2-mediated hyperimmune response has been constructed based on this knowledge. In addition, immunizing PIR-B−/− mice with T-independent (TI) antigens showed the enhanced IgM response compared with wild-type mice. It is thus found that PIR-B comprises an inhibitory ability for activation signaling via BCR under physiological conditions and it can down-regulate the size of the B-1 cell population. Moreover, immunizing PIR-B−/− mice with TD antigens (an alum adjuvant mixed with TNP-KLH which initiates Th2-type response and pertussis toxin) allowed the present inventors to find that the antibody titer of IgG1 was especially rose and IL-4 production in PIR-B-deficient mice was dominantly increased compared to wild-type mice. From these points of view, it has been shown that PIR-B-deficient mice exhibit Th-2-type prone humoral response, which might be caused by the impaired maturation of dendritic cells (DCs) in PIR-B−/− mice. Furthermore, in the present invention, based on this knowledge, a method for screening an inducer/promote or an inhibitor for Th2-mediated immune response or a promoter or an inhibitor for PIR-A function, a method for screening a therapeutic agent for allergosis, a method for diagnosis of allergosis and the like have been constructed.